Adenosine has been reported to have cardioprotective and neuroprotective properties. It is reportedly released from cells in response to alterations in the supply of or demand for oxygen, is said to be a potent vasodilator, and is believed to be involved in the metabolic regulation of blood flow. However, adenosine has a short half life (&lt;1 sec) in human blood, and therefore high doses of adenosine would need to be administered continuously to achieve effective levels. Adenosine has been reported to exhibit negative inotropic, chronotropic and dromotropic effects and to cause coronary steal by preferentially dilating vessels in nonischemic regions. Consequently, high doses of adenosine are toxic and severely limit its therapeutic potential. However, it is believed that by increasing adenosine concentration locally, i.e. at the target site within the target tissue, the beneficial effects of adenosine can be provided and the toxic systemic effects minimized.
Adenosine kinase is a cytosolic enzyme which catalyzes the phosphorylation of adenosine to AMP. Inhibition of adenosine kinase can potentially reduce the ability of the cell to utilize adenosine, leading to increased adenosine outside of the cell where it is pharmacologically active. However, the regulation of adenosine concentration is complex and involves other adenosine-metabolizing enzymes each with different kinetic properties and mechanisms of regulation.
A number of nucleosides including purine, pyrrolo[2,3-d]pyrimidine and pyrazolo[3,4-d]pyrimidine analogs have been evaluated for inhibition of adenosine kinase but were reported to have K.sub.i 's of greater than 800 nM (Caldwell and Henderson Cancer Chemother. Rep., 1971 2: 237-246; Miller et al., J. Biol. Chem., 1979, 254: 2346-2352). A few compounds have been reported as potent inhibitors of adenosine kinase with K.sub.i 's of less than 100 nM. These are the purine nucleosides, 5'-amino-5'-deoxyadenosine (Miller et al., J. Biol. Chem., 1979, 254: 2346-2352) and 1,12-bis(adenosin-N.sup.6 -yl)dodecane (Prescott et al., Nucleosides & Nucleotides, 1989, 8: 297), and the pyrrolopyrimidine nucleosides, 5-iodotubercidin (Henderson et al., Cancer Chemotherapy Rep. Part 2, 1972, 3: 71-85; Bontemps et al., Proc. Natl. Acad. Sci. USA, 1983, 80: 2829-2833; Davies et al., Biochem. Pharmacol., 1986, 35: 3021-3029) and 5'-deoxy-5-iodotubercidin (Davies et al., Biochem. Pharmacol., 1984, 33: 347-355; Davies et al., Biochem. Pharmacol., 1986, 35: 3021-3029).
Some of these compounds have been used to evaluate whether adenosine kinase inhibition might lead to increased extracellular adenosine concentrations. In rat cardiomyocytes, inhibition of adenosine deaminase by 2'-deoxycoformycin was reported to have no effect on adenosine release from the cells. In contrast, inhibition of ADA together with adenosine kinase by 5'-amino-5'-deoxyadenosine resulted in a 6-fold increase in adenosine release (Zoref-Shani et al., J. Mol. Cell. Cardiol., 1988, 20: 23-33). The effects of the adenosine kinase inhibitor alone were not reported.
Although the adenosine kinase inhibitors, 5'-amino-5'-deoxyadenosine and 5-iodotubercidin have been widely used in experimental models, the susceptibility of 5'-amino-5'-deoxyadenosine to deamination, and hence its potentially short half life, and the cytotoxicity of 5-iodotubercidin make their clinical utility limited and may limit interpretations based on these compounds. The pyrrolo[2,3-d]pyrimidines, 5-iodotubercidin and 5'-deoxy-5-iodotubercidin have been reported to cause pronounced general flaccidity and much reduced spontaneous locomotor activity in mice, interpreted to be skeletal muscle relaxation; to cause hypothermia in mice; and to decrease blood pressure and heart rate in anesthetized rats (Daves et al., Biochem. Pharmacol., 1984, 33: 347-355; Daves et al., Biochem. Pharmacol., 1986, 35: 3021-3029; U.S. Pat. No. 4,455,420). The skeletal muscle effects of these compounds have been poorly documented, while the other effects were considered significant toxicities.
Lyxofuranosyl adenine compounds have been reported. (Miller, R. L. et al., J. Biol. Chem., 1979, 254; 2346-2352; Agarwal, K. C. et al., Biochem. Pharmacol., 1979, 28, 501-510; Bennett, Jr., L. L. et al., Mol. Pharmacol., 1975, 11, 803-808). In particular, 9-.alpha.-L-lyxofuranosyl adenine has been reported to be a substrate for adenosine kinase, albeit with a much decreased efficiency relative to adenosine.
The commonly assigned U.S. Ser. No. 07/812,916, "Adenosine Kinase Inhibitors", filed Dec. 23, 1991 describes certain purine, pyrrolo[2,3-d] pyrimidine and pyrazolo[3,4-d]pyrimidine ribofuranosyl analogs which have activity as adenosine kinase inhibitors.